ISSN 2398-2969      

L-2-hydroxyglutaric aciduria

icanis

Synonym(s): L-2-HGA


Introduction

  • Inborn error of metabolism that affects nervous system.
  • Only known to affect humans until 2003 when the first canine case was reported in a Staffordshire Bull Terrier in the UK. Further cases have since been diagnosed in that breed in the US and Canada as well as a single case in a West Highland White terrier in the UK.
  • Humans with L-2-hydroxyglutaric aciduria (L-2-HGA) have delayed mental and motor development, seizures and ataxia. Disease is normally slowly progressive, though more rapidly deteriorating cases are seen, and some patients with intermittent acute deterioration are reported. Also, there is a rapidly fatal neonatal form of the disease.
  • Magnetic resonance imaging (MRI) of the brain in human patients is strongly suggestive of the disease and shows subcortical leukoencephalopathy (white matter disease), most easily seen on T2-weighted and FLAIR images. Disorder is confirmed by organic acid testing of cerebrospinal fluid, blood or urine with affected patients having very high levels of 2-HGA. Further tests are then performed to separate isomers of 2-HGA (D- and L-) which cause two distinct neurological diseases.

Pathogenesis

Etiology

  • Mutations within the gene L2HGDH on chromosome 14q22 encoding L-2-hydroxyglutaric acid dehydrogenase.
  • Mutation or change to the structure of the gene, probably occurred spontaneously in a single dog but once in the population has been inherited from generation to generation like any other gene.

Predisposing factors

General
  • Autosomal recessive mode of inheritance suggested by pedigree information collected to date.

Pathophysiology

  • Affected dogs have very distinct pathology (polioencephalomyelopathy) on MRI of brain L-2-HGA: MRI of brain.

Timecourse

  • Most affected dogs show slow progression (over several years), though some cases deteriorate more rapidly (over weeks to months).

Diagnosis

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Treatment

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Prevention

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Outcomes

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Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Scurrell E, Davies E, Baines E, Cherubini G B, Platt S, Blakemore W, Williams A & Schoniger A (2008) Neuropathological findings in a Staffordshire bull terrier with l-2-hydroxyglutaric aciduria. J Com Pathol 138 (2-3), 160-164 PubMed.
  • Penderis J, Calvin J, Abramson C, Jakobs C, Pettitt I, Binns M M, Verhoeven N M, O'Driscoll E, Platt S R, Mellersh C S (2007) L-2-hydroxyglutaric aciduria: characterisation of the molecular defect in a spontaneous canine model. J Med Genet 44 (5), 334-340 PubMed.
  • Garosi L S, Penderis J, McConnell J F & Jakobs C (2005) L-2-hydroxyglutaric aciduria in a West Highland white terrier. Vet Rec 156 (5)145-147 PubMed.
  • Abramson C J, Platt S R, Jakobs C, Verhoeven N M, Dennis R, Garosi L & Shelton G D (2003) L-2-Hydroxyglutaric aciduria in Staffordshire Bull Terriers. J Vet Intern Med 17 (4), 551-556 PubMed.

Other sources of information

  • Neurology/Neurosurgery Unit at the Animal Health Trust (+44 (0) 8700 502540;http://www.aht.org.uk/).
  • The Ohio State University School of Veterinary Medicine, Neurology/Neurosurgery Unit (614 292-3551).

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